1. Field of the Invention
The present disclosure relates in general to the field of pharmaceutical manufacturing, and more particularly, to thermokinetic mixing of active pharmaceutical ingredients (APIs) to produce novel dosage forms.
2. Description of Related Art
Current high-throughput molecular screening methods used by the pharmaceutical industry have resulted in a vast increase in the proportion of newly discovered molecular entities which are poorly water-soluble. The therapeutic potential of many of these molecules is often not fully realized either because the molecule is abandoned during development due to poor pharmacokinetic profiles, or because of suboptimal product performance. Also, in recent years the pharmaceutical industry has begun to rely more heavily on formulational methods for improving drug solubility owing to practical limitations of salt formation and chemical modifications of neutral or weakly acidic/basic drugs. Consequently, advanced formulation technologies aimed at the enhancement of the dissolution properties of poorly water-soluble drugs are becoming increasingly more important to modern drug delivery.
U.S. Pat. No. 4,789,597, issued to Gupta, is directed to the incorporation of chemically reactive agents on resin particles. Briefly, chemically reactive agents are locked to particles of suitable synthetic resins without wholly fluxing the resins. A high quality intermediate product is obtained having no premature reaction taking place, suitable for further techniques. The process includes the steps of intensively mixing and thermokinetically heating a batch of finely divided resin particles, with a chemically reactive agent, in an enclosed mixing chamber with a plurality of blades attached to arms rotating about a central axis within the chamber, and having a blade tip speed of at least about 18 meters per second, mixing the batch until the chemically reactive agent is locked to the resin particles, ensuring that temperature of the batch stays well below decomposition temperature of the reactive agent and below fluxing temperature of the resin particles, discharging the batch from the mixing chamber and cooling the discharged batch to avoid agglomeration of the resin particles.
U.S. Pat. No. 5,895,790, issued to Good, is directed to thermosetting a wide range of polymer blends. Briefly, a wide range of polymer blends and waste thermoset material can be recovered. One method of thermosetting a wide range polymer blends forms a homogenous and adaptable material. This material has a melt index of zero and a relatively predictable density. Very high levels of fibrous non-polymers may be added to the first material.
U.S. Pat. No. 6,709,146, issued to Little, is directed to a thermokinetic mixer and method of using the mixer. Briefly, a thermokinetic mixer has a mixing chamber with shaft projections removable at least in part and replaceable without cutting the projections from the shaft. In one embodiment, only a tip portion of such projections are removable and replaceable without such cutting. In another embodiment, shaft projections into the mixing chamber include a tooth having a substantially reticulated face forming a deflecting surface such that substantially all mixing chamber particles encountering the tooth strike are deflected at an incident substantially lateral angle from the deflecting surface.
U.S. Pat. No. 4,764,412, issued to Burns, discloses the use of a high speed mixer with a heated jacket about its vertical mixing chamber to first mix a set of components at 1700 rpm. The high speed mixer is stopped and after additional components are added, the rotational speed of the mixer is increased to 3400 rpm. Operation of the high speed mixer at a rotation speed of 3400 rpm generates heat which is advantageous in further processing of the mixture.
U.S. patent application Ser. No. 12/196,154, filed by the same inventor as this application and additional co-inventors, is directed to the application of thermokinetic compounding in the field of pharmaceutical manufacturing. Thermokinetic compounding is a method of thermokinetic mixing until melt blended. A pharmaceutical composition or composite made by thermokinetic compounding may be further processed according to methods well known to those of skill in the field, including but not limited to hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding into a final product. One embodiment is directed to a method of making a pharmaceutical composition that includes one or more active pharmaceutical ingredients with one or more pharmaceutically acceptable excipients by the thermokinetic compounding process. Another embodiment is directed to the composite comprising one or more APIs with one or more pharmaceutically acceptable excipients made by thermokinetic compounding is the final product.
Although the application of thermokinetic compounding in the field of pharmaceutical manufacturing offers significant advantages over other methodologies known in the pharmaceutical arts, it is possible that issues can arise in continuously melt blending certain heat sensitive or thermolabile components with certain non-thermolabile components using a thermokinetic mixer. Blending such a combination of components often requires using an elevated shaft speed or a reduced shaft speed for an extended processing time sufficient to impart complete amorphosity on the fully processed batch. In certain cases, this results in an exceedance of a limit temperature or heat input for an unacceptable duration. The batch thus experiences unacceptable degradation of the thermolabile components, as the substantial amount of heat absorbed by the entire batch results in thermal degradation of thermolabile components instead of increasing overall batch temperature. Substantially complete amorphosity is a measure well-known in the art of pharmaceutical preparation and processing; bioavailability may be significantly impaired in compositions lacking substantially complete amorphosity.